In Europe and the United States, ovarian cancer has been considered one of the five major cancers. In Japan, ovarian cancer kills about 4,000 people every year, and the number of casualties have rapidly increased by about 30-fold in the last 40 years, and it is one of the cancers most growing in number together with lung cancer and pancreatic cancer. Since ovarian cancer is present in the abdominal cavity, is difficult to diagnose early, and the capsule of ovarian cancer is easily broken and thus tends to metastasize early to the abdominal cavity, 60% of the patients die eventually, and thus it is one of the cancers having bad prognosis together with pancreatic cancer. Improved performance in therapy has been recognized due to the development of surgical methods and anti-cancer agents such as cisplatin and taxol, but none of the subsequent improvements in therapeutic regimens have been effective, and thus there is a need for the development of a new therapeutic method.
Recently, gene therapy has been tested in various cancers in which tumor suppressor genes, cytokine genes etc. are introduced into cancer cells to treat cancers, and its clinical usefulness has been confirmed. In ovarian cancer as well, it was found, gene therapy with a tumor suppressor gene p53 using an adenovirus vector exhibits clinical usefulness (reduction of tumor by 50% or more) in over 20% of recurrent ovarian cancers that did not respond to treatment with cisplatin or taxol (J. K. Wolf et al., Proceedings of American Society of Clinical Oncology, Vol. 19, May 2001, 382). Furthermore, oncolytic adenovirus has been developed aiming at the effect of cell lysis by adenovirus against tumor cells, and its usefulness has been confirmed in various cancers (Carla Heise et al., The Journal of Clinical Investigation, April 2000, Vol. 105, No. 7, 847-851; James R. Bischoff et al., Science, Vol. 274, 18 Oct. 1996, 373-376; J. Nemunaitis et al., Journal of Clinical Oncology, Vol. 19, No. 2, 2001, 289-298). Also, cell lysis effect by an oncolystic herpes virus using herpes virus has been reported (Miyatake S, et al., Gene Ther. 1999, Vol. 6, 564-572). However, with regard to virus vectors for use in such gene therapy, virus promoters such as CMV and RSV have conventionally been used, but an improved effect was not expected because the dose was limited due to the lack of tissue-specificity and hence to toxicity to the liver etc.
Gene therapy with vectors using organ-specific promoters is also being developed. Thus, clinical trials are about to start, for example, for gene therapy of bone metastasis of prostate cancer by a vector using an osteocalcin promoter (Shirakawa et al., Cancer Gene Therapy, 1998 September-October, 1998, 5(5), 274-280, 1998), for gene therapy of hemophilia by a vector using an albumin promoter (Alemany et al., J. Virol. Methods, 1997 November 68(2): 147-159), and for gene therapy of prostate cancer by a vector using a PSA promoter (Gotoh et al., J. Urol.1998 July 160(1): 220-229). However, no reports have been made on gene therapy using an ovarian cancer-specific gene promoter.
On the other hand, the IAI.3B gene has been reported as a gene purified and cloned by screening a cDNA library of an ovarian cancer cell line OVCA432 using an antibody generated in rabbits immunized with, as antigen, a protein in the high molecular weight region that abounds in the protein fraction specific to ovarian cancer in the pleural effusion of metastatic ovarian cancer (Campbell I. G., et al., Human Molecular Genetics, 1994, Vol. 3, No. 4, 589-594). It has also been reported that the open reading frame of the IAI.3B gene is 2990 bp, and the amino acid sequence of the protein encoded thereby comprises 966 amino acids with a molecular weight of 108 kd, that the protein encoded by the IAI.3B gene is a B-box protein having a transformation potential and the genomic gene is located in the telomere in the vicinity of the BRCA1 gene which is a tumor suppressor gene of ovarian cancer and breast cancer located at chromosome 17q21.1 (Campbell I. G., et al., Human Molecular Genetics, 1994, Vol. 3, No. 4, 589-594). It has also been suggested that the IAI.3B gene and the BRCA1 gene share the promoter region and the enhancer region (Melissa A. Brown et al., Nature, Vol. 372, 22/29 December 1994, 733), and that the regulatory mechanism of each gene expression plays an important role in the possible onset and proliferation of ovarian cancer (Melissa A. Brown et al., Oncogene, 1996, 12, 2507-2513). Though the activity of the promoter region of the BRCA1 gene has already been clarified (Smith et al., Genome Res., 1996 November; 6(11): 1029-1049), no reports have been made on the promoter activity of the IAI.3B gene.